Characterization of Octreotide-PLGA Binding by Isothermal Titration Calorimetry

Cationic peptides are well known to readily bind poly(lactic-co-glycolic acids) (PLGAs) with a carboxylic acid (-COOH) end group, which poses a significant challenge to develop PLGA-based delivery systems for peptide therapeutics. This binding has been considered as a critical step leading to the peptide acylation within PLGA-based formulations, which is also known to affect microencapsulation and release. Herein, we utilized nano isothermal titration calorimetry (NanoITC) to investigate the thermodynamics of peptide-PLGA binding in dimethyl sulfoxide (DMSO) using a model cationic octapeptide, octreotide, which contains two primary amino groups located at its N-terminus and lysine side chain at position five. ITC results of PLGAs with different lactic acid to glycolic acid ratios (50:50 to 100:0) revealed that the extent of the interaction with the octreotide was solely dependent on the availability of the acid end group of the PLGA. The binding constants (K-a) at 37 degrees C were determined in a narrow range from 1.33 to 1.72 X 10(4) M-1 with 0.59 to 0.66 binding stoichiometries irrespective of the lactic/glycolic acid ratio in the PLGA-COOH. Over 25-65 degrees C, the octreotide-PLGA-COOH interactions were found to be enthalpically favored (Delta H < 0) and entropically unfavorable (Delta S < 0). Hence, the interactions were characterized as enthalpically driven. At different sodium chloride (NaCl) levels, the sensitivity of thermodynamics of the interactions to the charge screening effect contributed by the NaCl unveiled the actual driving force of the octreotide -PLGA-COOH interactions is simple ion-pairing.